Amend had been drawing cartoons since childhood. They first saw print in the late 1970s, in his high school newspaper  tho his sometimes offbeat sense of humor wasn't always to the editors' liking. As a physics major at Amherst College, he was the regular editorial cartoonist in the school's semi-weekly paper; but by the latter part of his college career, his major creative outlet was a paper called Sidelines, which he co-published. It was only in his senior year (1983-84) that he began thinking seriously enough about cartooning to take an actual course in art. After he graduated, he had a succession of low-level cartooning or show-biz jobs, while submitting one strip after another to newspaper syndicates. Finally, Universal Press Syndicate bought FoxTrot. It debuted on April 10, 1988.

FoxTrot is about the five members of the Fox family  six, if you count the pet iguana, Quincy (no relation)  and their various friends and acquaintances. It's a character-driven strip, in that humor tends to arise more from the interactions of the characters themselves, rather than the situations they find themselves in. Bill Watterson, creator of Calvin & Hobbes, in his introduction to one of more than two dozen paperback collections of the strip, called this aspect "refreshing", and added, "This gives the world of FoxTrot a veracity other family strips lack. The Fox family has the resonance of honest observation."

The Fox family parents are Roger and Andy (short for Andrea), the Yin and Yang of competence. Roger is so lacking in even the basic skills of living, that the only job he's capable of holding is middle management in a corporation, while Andy is relatively sensible except for a tendency to get a little goofy about her passions, which include healthy eating. The two older kids, Peter (a high school junior) and Paige (a freshman) are relatively normal, considering they're teenagers, only more so. 10-year-old Jason is a computer genius, and one gets an impression he could take over the world if he thought it was worth the effort. Jason is the one who keeps Quincy as a pet.

Foxtrot eventually reached the dizzying circulation of over 1,000 newspapers, a level achieved by a precious few of the most popular strips.

After 18 years, Amend made a decision that producing both the daily and the Sunday versions of his comic was taking too great a toll on his own family. Most cartoonists in this position hire someone else to do one or the other, but Amend decided against diluting his personal vision for his creation. At the cost of a substantial portion of his own income, he ended the daily as of Saturday, December 30, 2006. Starting in 2007, FoxTrot is a Sunday-only comic.